The overall goal of this proposal is to clarify mechanistic pathobiological events underlying Lewy body (LB) dementias ? a dementing illness with cognitive impairment that affects more than a million Americans. An established molecular player in LB dementia is the small presynaptic protein ?-synuclein. Amongst a plethora of incriminating evidence, genomic multiplications and mutations of ?-synuclein are seen in families harboring these diseases; and it has been long recognized that understanding the mechanistic events that lead to ?-synuclein-mediated toxicity in LB dementia is of utmost importance. For over a decade, a primary focus in the field has been to decipher the normal function of ?-synuclein, with the ultimate goal of understanding transition to pathologic states. However, despite considerable effort, the precise mechanisms underlying the normal function of ?-synuclein, and early triggers leading to pathologic aggregation remain elusive. The basis of our proposal is a series of pilot experiments, where we uncovered novel roles for two functional partners of ?-synuclein, and we hypothesize that abnormalities in these associations are the initial pathologic triggers for LB dementias. Previous work from us and others has helped shape a consensus that ?-synuclein is a physiologic attenuator of neurotransmitter release, though underlying mechanistic events are unclear. In these previous studies, we proposed a model where ?-syn organizes into higher-order multimers that physiologically tether synaptic vesicles (SVs) ? leading to a diminution in SV-mobilization, SV-recycling, and consequently, neurotransmitter release. In new pilot experiments, we discovered novel roles for two other presynaptic proteins ? VAMP2 and synapsin ? in helping ?-synuclein attenuate neurotransmission. Eventually, our data led us to a working model where synapsin and VAMP2 play sequential roles in executing ?-synuclein function. Tenets of this model will be tested in Aims 1/2. Additionally, an emerging idea in the field is that disruption of physiologic associations might allow free ?-synuclein monomers to aggregate ? triggering pathology ? and that this might be one of the earliest pathologic events in disease; however, in vivo evidence is lacking. Leveraging our discoveries on functional ?-synuclein partners, Aims 2/3 will ask if a disruption of these associations might also accelerate pathology in cellular and animal models of LB dementias. Our aims are: Aim #1: Identify the role of VAMP2 in ?-synuclein mediated synaptic attenuation. Aim #2: Identify the role of synapsin in ?-synuclein mediated synaptic attenuation and pathology. Aim #3: Test the hypothesis that disrupting physiologic associations can trigger ?-synuclein pathology in vivo. Upon completion, our studies should reveal vital clues into the normal function of ?-synuclein, as well as events that trigger dementia and cognitive impairment in these devastating illnesses.